aInitial inclusion criteria included that women be enrollees of commercial or Medicare Advantage plans, be at least 18 years old, have a diagnosis code for breast cancer, have been treated with lumpectomy, and have any code for radiation therapy appearing within 12 months of lumpectomy, and treated between 2008 and 2013.

bExclusions applied sequentially. Patients could be excluded for more than 1 reason.

Harnett
A. Fewer fractions of adjuvant external beam radiotherapy for early breast cancer are safe and effective and can now be the standard of care: why the UK’s NICE accepts fewer fractions as the standard of care for adjuvant radiotherapy in early breast cancer. Breast. 2010;19(3):159-162.PubMedArticle

ResultsHypofractionated WBI increased from 10.6% (95% CI, 8.8%-12.5%) in 2008 to 34.5% (95% CI, 32.2%-36.8%) in 2013 in the hypofractionation-endorsed cohort and from 8.1% (95% CI, 6.0%-10.2%) in 2008 to 21.2% (95% CI, 18.9%-23.6%) in 2013 in the hypofractionation-permitted cohort. Adjusted mean total health care expenditures in the 1 year after diagnosis were $28 747 for hypofractionated and $31 641 for conventional WBI in the hypofractionation-endorsed cohort (difference, $2894; 95% CI, $1610-$4234; P < .001) and $64 273 for hypofractionated and $72 860 for conventional WBI in the hypofractionation-permitted cohort (difference, $8587; 95% CI, $5316-$12 017; P < .001). Adjusted mean total 1-year patient out-of-pocket expenses were not significantly different between hypofractionated vs conventional WBI in either cohort.

Conclusions and RelevanceHypofractionated WBI after breast conserving surgery increased among women with early-stage breast cancer in 14 US commercial health care plans between 2008 and 2013. However, only 34.5% of patients with hypofractionation-endorsed and 21.2% with hypofractionation-permitted early-stage breast cancer received hypofractionated WBI in 2013.

Introduction

Breast cancer accounts for the largest portion of national expenditures on cancer care, estimated to reach $158 billion in 2020.1 Breast conservation therapy is the most common treatment for early-stage breast cancer.2 Whole breast irradiation (WBI), recommended for most women after breast conserving surgery, reduces local recurrence and improves overall survival.3 Conventional WBI, comprising 5 to 7 weeks of daily radiation fractions (ie, treatments), has been the mainstay of treatment in the United States.

Hypofractionated WBI is a shorter duration treatment alternative to conventional WBI, comprising fewer but higher-dose fractions generally delivered over 3 weeks. In 2010, the Ontario Clinical Oncology Group published updated findings from a randomized trial with 12-year median follow-up showing that a 3-week hypofractionated WBI schedule yielded similar cancer control and breast cosmetic outcomes to a 5-week conventional WBI schedule.4,5 These findings reinforced the body of evidence supporting shorter radiation treatment schedules from 3 prior randomized trials (the United Kingdom’s Standardisation of Breast Radiotherapy (START)-A and START-B and the Royal Marsden Hospital/Gloucester Oncology Center trials).6- 9

In 2011, American Society for Radiation Oncology practice guidelines endorsed hypofractionated WBI as “equally effective for in-breast tumor control and comparable in long-term side effects” with conventional WBI for patients with early-stage breast cancer who satisfied 4 criteria: age 50 years or older, pathologic stage T1 or T2N0, no prior chemotherapy, and radiation dose heterogeneity higher or lower than 7% of prescription dose. The guidelines10 also permitted hypofractionated WBI for other patients with early-stage breast cancer, stating that “this guideline should not be interpreted to prohibit or oppose the use of hypofractionated WBI for patients not meeting all the criteria,” particularly among women younger than 50 years old, in whom “the available data did appear to support the equivalence of conventional and hypofractionated WBI.”

In 2013, the Choosing Wisely initiative, aimed at reducing low-value health care, encouraged physicians and patients undergoing breast conservation therapy to discuss the duration of WBI, a recommendation published as the START randomized trials11,12 reported long-term safety and clinical effectiveness of hypofractionated WBI.

Hypofractionated WBI increases convenience, reduces treatment burden, and lowers health care costs while offering similar cancer control and cosmesis to conventional WBI.4- 9 Furthermore, patients prefer shorter radiation treatment regimens.13 In a cohort of commercially insured patients with early-stage breast cancer, we examined the uptake and costs of hypofractionated WBI between 2008 and 2013—before and after the publication of the randomized evidence and practice guidelines.

Methods

Data Sources

The HealthCore Integrated Research Database links medical and pharmacy administrative claims and eligibility files from 14 commercial health care plans across the United States comprising 58 million covered lives between 2006 and 2013. In 2013, the HealthCore Database included 9.2 million adult women or 7.4% of US women. The data set includes claims data for commercial payer and Medicare Advantage enrollees and is thus an important research tool with which to investigate current use and costs of cancer care. This research was exempt from institutional review board approval because it involved a limited study database with masked patient identifiers.

Study Population

To identify women with an incident diagnosis of invasive breast cancer (≥2 claims with an International Classification of Diseases, Ninth Revision [ICD-9] diagnosis code of 174.x) who had breast conserving surgery (ie, lumpectomy) and subsequent WBI between January 1, 2008, and December 31, 2013, we used a validated algorithm,14- 16 examining the HealthCore database from January 1, 2006, to May 31, 2014 (Figure 1). This extended observation period includes continuous claims history of at least 24 months prior to diagnosis (to increase specificity for incident cases by excluding prevalent cases with prior claims for breast cancer–related diagnoses or procedures) and 3 months after radiotherapy start (to capture radiotherapy fraction billing codes during the WBI treatment course). We also included a 2-month claims run-out period through May 31, 2014; HealthCore analyses have shown that 90.2% of medical claims for services rendered in a given month become available for analysis within 2 months of the service date and 95.0% become available within 3 months.

We classified patients with early-stage breast cancer into hypofractionation-endorsed and hypofractionation-permitted cohorts. The hypofractionation-endorsed cohort most closely matched the group of patients for which practice guidelines concluded, with unanimous agreement among task force members, that “evidence supports the equivalence of hypofractionated with conventional WBI.”10 The hypofractionation-endorsed cohort included patients aged 50 years or older without prior chemotherapy or axillary lymph node involvement. The hypofractionation-permitted cohort included patients whose characteristics did not meet criteria for the first group for at least 1 of the following reasons: age younger than 50 years, prior chemotherapy, or axillary lymph node involvement. The practice guidelines neither endorsed nor prohibited hypofractionated WBI for this population.10

Primary and Secondary Outcomes

The primary end points were use of hypofractionated vs conventional WBI and associated health care expenditures and patient out-of-pocket expenses. We identified the course of WBI after breast conservation surgery and ascertained the number of radiotherapy fractions based on claims for radiation delivery.17 Health plans reimburse each radiotherapy fraction individually. We defined WBI as receipt of between 11 and 40 radiation fractions.

We defined hypofractionated WBI as 11 to 24 fractions (3-5 weeks of WBI) and conventional WBI as 25 to 40 fractions (5-8 weeks of WBI). Hypofractionated and conventional WBI could comprise whole breast radiation with or without a tumor bed boost, which are discretionary radiation treatments of 5 to 8 fractions.

Administrative claims data sets do not report measures of radiation dose heterogeneity, which is correlated with obesity, breast volume, and chest wall separation.10,18,19 Because of the possibility that patients in the hypofractionation-endorsed cohort were misclassified (eg, they had radiation dose heterogeneity measures outside of the criteria specified in the practice guidelines), we conducted a sensitivity analysis in which we restricted the hypofractionation-endorsed cohort to patients without ICD-9 diagnosis codes for obesity (278.0, V85.3, V85.4). The ICD-9 diagnosis codes for obesity have 99.1% specificity but 9.9% sensitivity for identifying patients with significant obesity (body mass index, ≥35, which is calculated as weight in kilograms divided by height in meters squared).20

We examined total health care expenditures paid by commercial insurers and patient out-of-pocket expenses during the initial phase of care,1 defined as the 1-year period from the date of the first claim with a diagnosis of breast cancer to 365 days after diagnosis. We calculated total health care expenditures by aggregating health plan payments for outpatient services (including chemotherapy and radiotherapy), diagnostic tests, emergency department visits, durable medical equipment, laboratory services, hospital services (inpatient hospital and skilled nursing facilities), and physician services. Prescription drugs were included if billed through plans’ medical benefits; however, prescription drugs billed through plans’ pharmacy benefits were not captured. We calculated patient out-of-pocket expenses by summing deductible, co-payment, and coinsurance amounts.

In secondary analyses, we evaluated radiotherapy-related expenditures during the episode of radiotherapy, defined as the 3.5-month period from 15 days before to 90 days after radiotherapy start.17 We chose the 90-day window to ensure that enough time elapsed to capture radiotherapy-related expenditures from treatment courses that last up to 8 weeks in routine practice. The full 3.5-month radiation episode was captured within the 1-year postdiagnosis total health care expenditures for 98% of patients. We calculated radiotherapy-related expenditures according to prior methods by summing the costs of claims for radiotherapy simulation, planning, physics, delivery, and management (Current Procedural Terminology [CPT] codes 77261 and 77999).21 Expenditures were adjusted for inflation to 2013 using the Medical Care Services component of the consumer price index.

Other Variables

Patient, clinical, and demographic characteristics included year of treatment, age, comorbid disease,22 history of chemotherapy before and after lumpectomy, axillary lymph node involvement (defined as nodal surgery between cancer diagnosis and radiation), practice setting, and use of intensity-modulated radiotherapy (IMRT). IMRT is a more expensive and complex form of radiotherapy that is sometimes used to reduce radiation dose heterogeneity or dose to normal structures relative to non-IMRT techniques.23 Other contextual variables included density of radiation oncologists by hospital service area, population density of county of residence (categorized as urban or rural), median household income in the county of residence (US dollars), and patients with less than high school educational attainment in the county of resident (percentage).24

Statistical Analysis

We performed multivariable logistic regression to evaluate temporal trends in the use of hypofractionated relative to conventional WBI over the study period, adjusting for patient, clinical, demographic, and contextual variables. Separate multivariable models were constructed for the hypofractionation-endorsed and hypofractionation-permitted cohorts. We report the total number of patients, the percentage receiving hypofractionated and conventional WBI, and adjusted odds ratios (ORs) with 95% CIs for each covariate. The adjusted ORs represent the ratio of the odds of receiving hypofractionated WBI in one group (eg, women aged, 55-59 years or other age quintile) relative to the odds of receiving hypofractionated WBI in a reference group (eg, women aged, 50-54 years), adjusted for patient, clinical, demographic, and contextual variables in multivariable models. Diagnosis year was included in multivariable models as a continuous variable. The levels of missingness in the cohorts were minor (<2%); we retained patients with missing data to estimate rates of hypofractionated WBI but excluded them from multivariable models.

We compared mean expenditures between the hypofractionated and conventional WBI groups using generalized linear models with gamma distribution and log-link function. We estimated adjusted mean differences by first exponentiating the model-based linear predictions for the average hypofractionated and conventional WBI groups separately and then calculating their arithmetic difference. Analyses were conducted using SAS version 9.2 (SAS Institute Inc). Statistical significance was set at .05.

Results

The definition of the study population and reasons for exclusions are detailed in Figure 1. The final analytic cohorts included 15 643 patients: 8924 in the hypofractionation-endorsed cohort and 6719 in the hypofractionation-permitted cohort.

In the hypofractionation-endorsed cohort, the mean (SD) age was 62.7 years (8.9 years) and 5879 patients (66.0%) were younger than 65 years (Table 1). In the hypofractionation-permitted cohort, the mean (SD) age was 52.7 years (9.7 years), 3161 patients (47.0%) were younger than 50 years, 1372 (20.4%) had axillary lymph node involvement, 715 (10.6%) received chemotherapy prior to breast conserving surgery, and 4005 (59.6%) received chemotherapy prior to WBI (Table 2).

In the hypofractionation-endorsed cohort, the proportion of patients who received hypofractionated WBI increased from 10.6% (95% CI, 8.8%-12.5%) in 2008 to 34.5% (95% CI, 32.2%-36.8%) in 2013, with more pronounced uptake between 2012 and 2013 (Figure 2). The median number of daily fractions delivered was 32 (interquartile range [IQR], 27-33), corresponding to a 7-week treatment regimen; 68.8% of patients received 30 or more fractions (eFigure 1 in the Supplement). In sensitivity analysis restricted to 1340 of 1625 patients in 2013 in the hypofractionation-endorsed cohort without diagnosis codes for significant obesity, the proportion of patients who received hypofractionated WBI was 34.8% (95% CI 32.2%-37.3%).

In the hypofractionation-permitted cohort, the proportion of patients who received hypofractionated WBI increased from 8.1% (95% CI, 6.0%-10.2%) in 2008 to 21.2% (95% CI, 18.9%-23.6%) in 2013 (Figure 2). The median number of daily fractions delivered was 33 (IQR, 30-33); 78.0% of patients received 30 or more fractions (eFigure 2 in the Supplement).

In adjusted analyses, younger women were significantly less likely to receive hypofractionated relative to conventional WBI in the hypofractionation-endorsed cohort (Table 1). For example, 15.4% (95% CI, 13.7%-17.1%) of women aged 50 to 54 years received hypofractionated WBI vs 23.5% (95% CI, 20.6%-26.5%) of women aged 70 to 74 years (P < .001) and 29.4% (95% CI, 26.8%-32.2%) of women older than 75 years (P < .001). In the hypofractionation-permitted group, age was not significantly associated with hypofractionated WBI (Table 2).

Adjusted mean total health care expenditures in the year after diagnosis were $28 747 for hypofractionated and $31 641 for conventional WBI in the hypofractionation-endorsed cohort (difference, $2894; 95% CI, $1610-$4234; P < .001) and $64 273 for hypofractionated and $72 860 for conventional WBI in the hypofractionation-permitted cohort (difference, $8587; 95% CI, $5316-$12 017; P < .001; Table 3). Of mean total health care expenditures in the year after diagnosis, hypofractionated WBI was associated with savings of 9.1% (95% CI, 5.3%-12.8%) in the hypofractionation-endorsed cohort and 11.8% (95% CI, 7.6%-15.8%) in the hypofractionation-permitted cohort.

Among women enrolled in 14 US commercial health plans aged 50 years or older for whom randomized trials and practice guidelines have endorsed hypofractionation after breast conserving surgery as comparable in clinical efficacy, cosmesis, and toxicity with conventional WBI, 34.5% received hypofractionated WBI in 2013. Younger women were significantly less likely to receive hypofractionated WBI. Among the cohort of women for whom practice guidelines have permitted hypofractionation, 21.2% received hypofractionated WBI in 2013. In both populations, the proportion of patients receiving hypofractionated WBI increased significantly between 2008 and 2013. Mean total health care expenditures for patients receiving hypofractionated WBI were about 10% less than for patients receiving conventional WBI.

Our findings highlight differences in international care patterns for early-stage breast cancer. In 2008, of patients of any age who received WBI without regional lymph node irradiation in Ontario, Canada, 71% received hypofractionated WBI.25 In Ontario, 6.3% of patients received 30 or more fractions. Conversely, of 14 271 commercially insured patients of any age without regional lymph node involvement in our study sample, 72.1% (95% CI, 71.4%-72.9%) received 30 or more fractions. In Ontario, 52.7% of patients younger than 50 years without regional lymph node involvement received hypofractionated WBI; in our data, 13.0% (95% CI, 11.7%-14.2%) of patients younger than 50 years without regional lymph node involvement did. In the United Kingdom, most patients with early-stage breast cancer have received hypofractionated WBI since 2009, when the National Institute for Health and Clinical Excellence (NICE) released guidance recommending hypofractionated WBI as a care standard.26

Because hypofractionated WBI involves fewer radiation fractions, radiotherapy-related expenditures were also significantly lower for hypofractionated WBI. Radiotherapy-related savings associated with hypofractionated WBI were qualitatively similar between the cohorts even though total health care expenditures were higher in the hypofractionation-permitted cohort. Patients in the hypofractionation-permitted cohort had greater disease severity; 70.2% received chemotherapy prior to breast conserving surgery or WBI.

In the United States, although the 2011 practice guidelines concluded that hypofractionated and conventional WBI were “equally effective for in-breast tumor control and comparable in long-term side effects” for selected women, the guidelines stopped short of recommending hypofractionated WBI as a care standard to be used in place of conventional WBI.10 The absence of a clear recommendation may have contributed to slower uptake of hypofractionation in the United States than in other countries.25 In 2013, we observed more pronounced uptake of hypofractionation; evaluation of future treatment patterns will be important to document whether or not this trend reflects the beginning of more widespread adoption.

Radiation oncologists have expressed apprehension about the possibility of long-term toxic effects associated with shortened treatment schedules.27 A survey conducted in 2008 of 1807 women identified from mammography databases and 363 radiation oncologists showed that nearly twice as many women preferred hypofractionated WBI to conventional WBI but only half of radiation oncologists offered hypofractionated WBI.13 In 2013, the Choosing Wisely Top 5 initiative for radiation oncology strongly encouraged discussion of the duration of WBI among patients and physicians and may promote better alignment of physician and patient preferences.12

Research supports benefits to patients with the use of hypofractionated WBI. Four randomized trials, each with at least 10 years’ follow-up, have demonstrated similar cancer control and breast cosmetic outcomes between hypofractionated and conventional WBI.4,8,9,11 Our findings also showed that increased use of hypofractionated WBI among commercial enrollees was associated with lower total expenditures on early-stage breast cancer in the year after diagnosis. Patients may not share directly in savings; we found that commercial enrollees had high out-of-pocket expenses irrespective of treatment largely because they had reached their out-of-pocket maximums in the first year after breast cancer diagnosis. However, patients and their families may accrue indirect economic benefits, including reduced time away from work and home. Indirect savings and productivity benefits are considerable sources of economic gain28 and may motivate calls for greater use of hypofractionated WBI.

Our study has limitations. First, claims-based identification of incident early-stage cancer and WBI may be subject to misclassification bias, although we used previously validated ascertainment methods.14- 16

Second, we were unable to ascertain pathologic tumor or nodal stage or radiation dose heterogeneity measures. Therefore, it is possible that patients in the hypofractionation-endorsed cohort were misclassified. Such misclassification would bias the hypofractionated WBI estimate downward. However, pathologic T- or N-stage misclassification is likely to be infrequent because patients in the hypofractionation-endorsed cohort had neither axillary lymph node-directed surgery nor chemotherapy.

Our findings also held among a restricted group of patients in the hypofractionation-endorsed cohort with significant obesity. Although this sensitivity analysis underestimated the prevalence of obesity, the hypofractionated WBI rate among patients with significant obesity was similar to the rate among patients without obesity diagnosis codes, suggesting that the possible effect of radiation dose heterogeneity misclassification is likely small. We were also unable to ascertain histology, surgical margins, breast cancer tumor and receptor markers or laterality, or radiation fields and dose.

Third, we allowed a 2-month claims run-out period in 2014 to increase data completeness; however, missing claims data are possible in the last 1 to 2 months of analysis, which could bias estimates of hypofractionated WBI upwards. When we excluded patients in the hypofractionation-endorsed cohort whose radiotherapy started in the last 3 months of 2013, the estimate of hypofractionated WBI in 2013 declined from 34.5% to 32.2%.

Fourth, we cannot determine a causal link between increased hypofractionated WBI and publication of the randomized trials or practice guidelines based on our observational cohort.

Conclusions

Hypofractionated WBI after breast conserving surgery increased among women with early-stage breast cancer in 14 US commercial health care plans between 2008 and 2013. However, only 34.5% of women with hypofractionation-endorsed and 21.2% with hypofractionation-permitted early-stage breast cancer received hypofractionated WBI in 2013. Hypofractionated WBI was associated with lower total and radiotherapy-related health care expenditures.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Bekelman, Sylwestrzak, Barron, Liu, Epstein.

Obtained funding: Bekelman, Barron, Malin.

Administrative, technical, or material support: Sylwestrzak.

Study supervision: Bekelman, Barron, Malin, Emanuel.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Liu and Barron and Ms Sylwestrzak reported that they are employees of HealthCore, which is a wholly-owned Anthem subsidiary. Dr Malin reported that she is an employee of Anthem.

Funding/Support: Dr Bekelman received support from grant K07-CA163616 from the National Cancer Institute. Anthem provided funds to support research at HealthCore, a wholly-owned Anthem subsidiary.

Role of the Funder/Sponsor: Anthem had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The interpretation and reporting of these data are the sole responsibility of the authors.

Additional Contributions: We thank Nandita Mitra, PhD, of the University of Pennsylvania, for methodological discussion during the revision process. Dr Mitra was not compensated for her contributions.

Correction: This article was corrected December 18, 2014, because the sponsoring company changed its name to Anthem.

Harnett
A. Fewer fractions of adjuvant external beam radiotherapy for early breast cancer are safe and effective and can now be the standard of care: why the UK’s NICE accepts fewer fractions as the standard of care for adjuvant radiotherapy in early breast cancer. Breast. 2010;19(3):159-162.PubMedArticle